Effects of IPLEX in Myotonic Dystrophy Type 1 (DM1)

1. Effects of IPLEX in Myotonic Dystrophy Type 1 (DM1) Muscle Study Group Annual Meeting 9/16/2008, Beaver Hollow, NY Richard T. Moxley, III, MD

2. Acknowledgements University of Rochester Medical Center • Principal investigator: Richard Moxley, III, MD • Co-investigators: Charles Thornton, MD, Chad Heatwole, MD, Rabi Tawil, MD, Eric Logigian, MD, Stephen Welle, PhD • Biostatistician : Michael McDermott, PhD • Clinical Evaluator: Shree Pandya, MS, PT and Katy Eichinger, PT • Study coordinators: Jim Hilbert, MS, Christine Quinn, MS and Alexis Smirnow • Data management: Bill Martens. • Research administration: Nancy Merriman and Tracy Forester • Research assistants: Roxanne Cannarozzo and Karen Berk. • Neuro-Ophthalmology: Deborah Friedman, MD University of Texas Health Science Center, San Antonio. • Independent Medical Monitor: Carlayne Jackson, MD

3. Acknowledgements • NIH Wellstone Muscular Dystrophy Cooperative Research Center (MDCRC) staff, leaders, and members of the DSMB.

4. Muscle Wasting in DM1 • Proposed causes: • Insulin resistance, gonadal insufficiency, decreased growth hormone release. • Unsuccessful trials of • insulin, testosterone, and recombinant human growth factor (rhGH). • Promising results of rhIGF-1 (recombinant human insulin like growth factor) (Vlachopapadopoulou, 1995), • Improved insulin action, decreased body fat, increased plasma testosterone (n=7), • But, clinically significant side effects and short half-life.

5. Insulin Like Growth Factor 1 (IGF-1) • Family of 6 binding proteins (BPs): • At least 5 of 6 BP’s form binary complex with IGF-1. • Ternary complex comprised of IGF-1, IGFBP-3, and an acid-labile subunit (ALS). • 95% of circulating IGF-1 is bound to ternary complex. • Small fraction of IGF-1 is unbound or “free” in circulation.

6. IGF Schematic: figure from Denley at el. (2005).

7. Background: IPLEX • IPLEX (Insmed, Inc) is rhIGF-1 complexed to rhIGF-BP3 • Longer half-life and better safety profile compared to rhIGF-1. • IPLEX has been well-tolerated and effective in: • Severe primary IGF-1 deficiency, • HIV associated adipose redistribution syndrome (HARS), • Severe insulin resistance, • Insulin dependent type-II diabetics, • Elderly women with hip fractures.

8. Innovative Approach • Preparation of IGF-1 that may bypass insulin resistance and other anabolic defects that hamper muscle loss in DM1.

9. Study Design • Primary Aim: To determine safety and feasibility of daily SC injection of IPLEX as treatment for muscle wasting and weakness in DM1. • Subjects: 15 DM1 patients (21-60 yrs of age) each for initial “Dose Escalation” trial.

10. IPLEX 1.0 mg/kg IPLEX 1.0 mg/kg Off study drug IPLEX 0.5 mg/kg 0 2 4 6 8 10 12 14 16 18 20 22 24 40 28 WEEKS Design for 24 week Dose Escalation Trial of IPLEX IPLEX 2.0 mg/kg

11. Cohort of Patients • Cohort 1: Completed pilot study (n=6). • 8 weeks of 0.5 mg/kg/day and 16 weeks of 1.0 mg/kg/day of IPLEX. • DSMB requested that we obtain data on the relationship between blood levels of IGF-I (at 0.5 mg/kg/day and 1.0 mg/kg/day) and any adverse events before moving to a 3-step dose escalation. • Cohort 2: Completed dose escalation of 0.5, 1.0, 2.0 mg/kg/day (8 weeks each) of IPLEX (n=9).

12. Outcome Measures • Primary: Safety and tolerability. • Secondary: • clinical laboratory data, • lean body mass and fat mass (DEXA), • muscle strength (QMA and MMT), • myotonia (grip and electrically evoked), • IGF-1, IGF-2, and IGF-BP3 levels, • gastrointestinal and cognitive measurements.

13. Timeline • 2003-2005 • Completed start-up procedures, manual, etc. • 2005-2007 • Enrolled patients. • September 2007 • Presented at the 6th International Myotonic Dystrophy Consortium (IDMC) Meeting; • Presented preliminary data on the first 6 patients. • April 2008 • Completed all treatment and post-treatment visits.

14. Results • Adverse Events and safety profile. • Total and free IGF values. • Muscle mass as measured by DEXA.

15. Adverse Events (AE) • 1 serious AE (SAE) occurred in the off-drug phase: • deemed unrelated (gallbladder removed). • No SAEs related to study drug. • 1 moderate, possibly related AE: • papilledema and intracranial hypertension that resolved without sequelae.

16. Adverse Events • 103 mild AEs: • 42% (n=44/105) were not related, • 45% (n=47/105) were possibly related, • 13% (n=14/105) were probably related. • 14 AEs probably related to study drug: • 2 AEs of light headedness, • 3 AEs of hypoglycemia, • 9 injection site reactions (n=8 patients).

17. Safety Profile • Of the 9 injection site reactions, • 7 occurred at first dose (0.5 mg/kg/day); • 2 occurred at second dose (1.0 mg/kg/day); • 0 occurred at third dose (either 1.0 or 2.0 mg/kg/day). • Laboratory and imaging results indicated IPLEX was safe and well tolerated.

18. Total IGF-1 values Fig 1: Mean total IGF-I levels analyzed. Mean normative range indicated as dashed line; 100 – 308ng/mL (Esoterix). n=15 n=5 n=9 n=15 n=15 n=15 n=15 0.5 mg/kg 1.0 mg/kg 1.0 mg/kg 2.0 mg/kg

19. Free IGF-1 values Fig 2: Mean free IGF-I levels analyzed to date. Mean normative range indicated as dashed line; 0.65 – 5.2ng/mL (Juul et al., 1997). n=15 n=15 n=5 n=9 n=15 n=15 n=15 0.5 mg/kg 1.0 mg/kg 1.0 mg/kg 2.0 mg/kg

20. Lean Muscle Mass: Cohort 1 Fig 3: Change in mean lean muscle mass (g) compared to baseline and measured by Dual Energy X-ray Absorptiometry (DEXA) (n=6). * p<0.05 On IPLEX Off IPLEX Lean Mass (g) Post 4 wks Post 16 wks 8 wks 16 wks 24 wks

21. Lean Muscle Mass: Cohort 2 Fig 4: Change in mean lean muscle mass (g) compared to baseline and measured by Dual Energy X-ray Absorptiometry (DEXA) (n=9). * p<0.05 On IPLEX Off IPLEX Lean Mass (g)

22. Summary • IPLEX was safe and well-tolerated in DM1 (n=15 patients). • Encouraging trends in a variety of endpoint measures, including patient reported outcomes.

23. A Catalyst For Future Study • These initial pilot studies have led to a multi-center collaborative study using methods established by our NIH Wellstone MDCRC dose escalation trial.

24. Phase II Trial • Led by Insmed, Inc, with funding through Insmed and Muscular Dystrophy Association (MDA) Translational Research Corporate Grant. • 12 sites participating in the randomized, placebo-controlled, double-blind clinical study of IPLEX in ~70 DM1 patients.

25. IPLEX 1.0 mg/kg/day or placebo Study Design Endpoints: • Endurance • Ambulation • Cognitive function • Insulin resistance • Cholesterol and triglycerides • Muscle function and strength • Pain • Gastrointestinal function • Quality of life 0 4 8 12 16 20 24 WEEKS

26. Progress and Collaborations • Current Phase II trial is beyond the scope of traditional Wellstone funding. • NIH Wellstone MDCRC funding has nurtured collaboration between industry, patient advocacy groups, and medical centers. • What other studies can develop?

27. Future Questions • What measures of IGF-1 and/or related proteins best indicate a therapeutic response? • Additional measures may include other IGF BPs, sex steroid BP, growth hormone, and other pituitary-hypothalamic axis hormones. • What are the best endpoint measures in our optimal dose treatment trial?

28. Extra slides, drafts

29. Lean Muscle Mass (Cohort 1) Fig 2: Mean lean muscle mass (kg) as measured by Dual Energy X-ray Absorptiometry (DEXA) (n=5 for week 24; n=6 all other weeks). On IPLEX Off IPLEX Lean Mass (kg)

30. Lean Muscle Mass (change each visit) Fig 2: Mean lean muscle mass (kg) as measured by Dual Energy X-ray Absorptiometry (DEXA) (n=5 for week 24; n=6 all other weeks). On IPLEX Off IPLEX Lean Mass (g)